Dynamic Analysis of Tumor and Microenvironment in Patients Undergoing Immunotherapy

项目摘要/摘要 利用免疫系统抗击癌症已被证明非常有效，但大多数患者 都是用免疫疗法治疗不起作用。我们对是什么决定了对 免疫疗法仍然很差。对癌细胞的免疫识别和破坏发生在 肿瘤微环境(TME)，但由于缺乏合适的人体TME研究一直比较困难 临床前模型，获取足够的患者肿瘤组织的挑战，以及缺乏分析工具来 研究癌症和免疫系统之间复杂的相互作用。在这份提案中，我们将直接 研究免疫疗法随时间在患者TME中产生的变化 滤泡性淋巴瘤原位接种(ISV)两个试验中的连续多点肿瘤活检方法。我们是 利用单细胞基因组学和多参数组织学平台的技术进步来研究 有限的深度样本以及生物信息学的进步，使我们能够提取重要的信息 来自大型复杂数据集，目标是在治疗前和治疗前确定关键的肿瘤-免疫相互作用 治疗过程中免疫反应的演变。我们将重点介绍T细胞表型和克隆型 ISV后与肿瘤反应有关的变化(目标1)，即肿瘤细胞对ISV的反应是否会增强 抗肿瘤免疫的产生(目标2)，以及TME中细胞之间的相互作用(目标3)。这 全面的方法将对免疫治疗成功的决定因素产生关键的见解。 这项工作将由Tanaya Shree博士承担，他是纽约大学肿瘤学系的研究员 斯坦福大学医学院。Shree博士在康奈尔/洛克菲勒完成了医学博士和博士学位的双学位课程 她在那里发现肿瘤相关巨噬细胞有助于小鼠的乳房 癌症在化疗中存活，抑制关键的巨噬细胞功能可以改善化疗 功效。在斯坦福大学，Shree博士继续研究癌症和免疫系统，已经开发出两种 研究人员发起的免疫治疗试验，研究了淋巴瘤幸存者的免疫健康，并建立了 在免疫学和高维分析方面的专业知识，用于研究免疫治疗的机制。 Shree博士将在这项工作中由Ronald Levy医学博士和Hanlee Ji医学博士指导。两人都是内科科学家 他们在癌症免疫治疗和基因组学领域做出了重大贡献，并 指导了许多成功的独立研究人员。此外，一个由杰出顾问组成的委员会， 由Crystal Mackall博士、Garry Nolan博士和Ash Alizadeh博士组成，将指导她的研究和职业生涯 发展。Shree博士的培训计划侧重于高级免疫学的讲授和实践培训， 生物信息学和生物统计学，以补充她在生物医学研究方面的丰富技能和经验。

PROJECT SUMMARY / ABSTRACT Harnessing the immune system to fight cancer has proven to be remarkably effective, but most patients who are treated with immunotherapy do not respond. Our understanding of what determines the response to immunotherapy remains poor. Immune recognition and destruction of cancer cells occurs at the level of the tumor microenvironment (TME), but the human TME has been difficult to study due to a lack of suitable preclinical models, the challenges in acquiring adequate patient tumor tissues, and a lack of analytic tools to study the complex interplay between cancer and the immune system. In this proposal, we will directly investigate the changes immunotherapy produces in the TME of patients over time by utilizing samples from a serial multi-site tumor biopsy approach in two trials of in situ vaccination (ISV) in follicular lymphoma. we are leveraging technological advances in single cell genomics and multiparameter histology platforms to study limited samples in great depth as well as bioinformatics advances that allow us to extract important information from large complex datasets with a goal of identifying the key tumor-immune interactions before treatment and the evolution of immune responses with treatment. We will focus on how T-cell phenotypes and clonotypes change after ISV and relate to tumor responses (Aim 1), on whether tumor cell responses to ISV may enhance the generation of anti-tumor immunity (Aim 2), and on interactions between cells in the TME (Aim 3). This comprehensive approach will yield critical insights into the determinants of successful immunotherapy. This work will be undertaken by Tanaya Shree, MD PhD, a fellow in the Department of Oncology at the Stanford University School of Medicine. Dr. Shree completed a dual MD/PhD program at Cornell/ Rockefeller University/ Sloan-Kettering where she discovered that tumor-associated macrophages helped murine breast cancer survive chemotherapy and that dampening critical macrophage functions could improve chemotherapy efficacy. At Stanford, Dr. Shree continues to investigate cancer and the immune system, having developed two investigator-initiated immunotherapy trials, studied the immune health of lymphoma survivors, and established expertise in immunology and high-dimensional assays for studying mechanisms of immunotherapy. Dr. Shree will be mentored in this work by Ronald Levy, MD, and Hanlee Ji, MD. Both are physician-scientists who have made significant contributions to the fields of cancer immunotherapy and genomics and have mentored numerous successful independent researchers. In addition, a distinguished committee of advisors, consisting of Drs. Crystal Mackall, Garry Nolan, and Ash Alizadeh, will guide her research and career development. Dr. Shree’s training plan focuses on didactic and practical training in advanced immunology, bioinformatics, and biostatistics to complement her substantial skills and experience in biomedical research.